Two Cycles of Chemotherapy Modulate Itaconic Acid Levels via ATF3/TET2/NF-κB Pathways in Ovarian Cancer Among Han Chinese Women

Abstract Background The optimal chemotherapy cycles after debulking surgery in ovarian cancer (OC) remain unclear. This prospective cohort was aimed to define metabolic changes induced by chemotherapy, determine the ideal regimen, and assess longitudinal effects. Methods Metabolites between treatment-naïve OC patients (n = 26) and age-matched healthy controls (n = 30) were identified by gas chromatography-mass spectrometry (GC-MS). Chemotherapy-related signaling molecules were quantified via ELISA. Results Our analysis identified 38 differentially expressed metabolites, including critical intermediates in the tricarboxylic acid (TCA) cycle and revealed significant reductions in five TCA cycle intermediates, namely itaconic acid, citric acid, fumaric acid, cis-aconitic acid, and malic acid, in OC patients compared to controls. Following the first chemotherapy cycle, global metabolomic profiling showed minimal changes; however, targeted analysis indicated an increase in itaconic acid levels prior to the second chemotherapy cycle. Remarkably, after two chemotherapy cycles, itaconic acid concentrations normalized to levels comparable to those in healthy controls, suggesting metabolic recovery. Furthermore, significant inverse correlations were observed between HE4 levels and the concentrations of the five TCA cycle intermediates, highlighting the potential of these metabolites as biomarkers. Mechanistic studies revealed that two cycles of chemotherapy restored metabolic homeostasis, normalizing itaconic acid levels and reactivating the ATF3/TET2/NF-κB signaling pathway to levels seen in healthy participants. Conclusions Two chemotherapy cycles may represent an optimal therapeutic strategy following complete cytoreduction, offering novel insights into chemotherapy-induced metabolic reprogramming and potential directions for both clinical decision-making and mechanistic research in OC management. Trial registration: ClinicalTrials.gov ID: ChiCTR2300069160.